These studies are designed to extend our information about the circadian control of hard tissue metabolism in growing animals, and to gain insight about the short and long term consequences of pharmacologic intervention at different clock hours in a 24 hour day. In rats, we have developed a detailed profile of biochemical events in cartilage and bone which can be referred to the phasing of certain metabolic parameters in human bone biology. In the ad-lib fed rat, at least, we can now predict when (day or night) regional growth and remodelling phases occur at maximal and minimal rates. Research has also developed preliminary evidence that there is more than a single synchronous population of osteogenic cells on the surfaces of trabecular and cortical bone.. that these populations are out-of phase with one another by 24 hours in the rabbit but still may operate in a circadian fashion during their active periods. Moreover, chronopharmacologic studies involving (1) fracture, (2) systemic and intra-articular corticosteroid treatment, and (3) the EDTA-induced (parathyroid) response to hypocalcemia have all indicated that induced metabolic alterations in bone have the most far-reaching consequences when they are timed to coincide with the hours of most active cell and tissue growth. Our major objectives are now to explore the variations in the chronoresponsivity of bone cells and chondrocytes in laboratory animals to other metabolic stressors. We will test a variety of endocrine agents that provoke either osteopenic or osteosclerotic changes, and determine if chronotherapeutic regimens with anabolic hormones and EHDP might reduce the severity of post-immobilization osteopenia. High resolution autoradiographic technique will be applied to learn if there are periodic differences during the day in the size and histotypic character of the pool of steroid and non-steroid target cells in the skeleton. A major effort is directed toward study of the endogenous (photoperoidic) or exogenous (steroids or meal-timing) control of the skeleton as a circadian system...to determine the feasibility of temporally shifting the phase of skeletal rhythms as an adjunct to the management of patient populations.